Use of extended release formulation of therapeutic agents can improve patient compliance, reduce hospital stays and hospital costs and, therefore, result in costs savings to the patient and the healthcare system. The market for such extended release formulations are expected to exceed several billion dollars annually in the U.S. alone.
A useful method, by which long lasting therapy can be achieved, is by a single application of a depot formulation. The depot can be optimized for injection, infiltration into an incision, implantation or topical application. In a depot formulation, a therapeutic agent is formulated with carriers providing a gradual release of the therapeutic agent over a period of several hours to several days, or longer. Depot formulations are generally based upon a biodegradable matrix which gradually undergoes degradation or disperses thus releasing the therapeutic agent.
Hence, the advantage of depot formulations is that active therapeutic agents are released gradually over long periods without the need for repeated dosing. These formulations are thus highly suitable for situations where continuous therapeutic effect is desirable, where around-the-clock dosing via an injection pump-type dosing device that delivers medication into the veins (intravenously, the most common method), under the skin (subcutaneously), or between the dura mater and the backbone (epidurally).
Many depot formulations rely on particles incorporated into liposomes or microspheres for encapsulation of the therapeutic agent. Liposomal depot formulations, however, are difficult to manufacture, are extremely sensitive to surface active agents, have limited shelf-life or require special storage conditions and a sub-ambient temperature for storage. Due to their particle size and fragile nature which prevents the use of common sterilization methods such as filtration, irradiation or autoclaving, liposomal multivesicular depot formulations are usually made under aseptic conditions which make the manufacturing process cumbersome and costly. In addition, liposomal depot formulations generally provide extended release of the therapeutic agent for up to 12 hours only.
Various products are described with drugs incorporated into microspheres in oil based carriers.
For example U.S. Pat. No. 7,547,452 to Atkins et al. provides sustained-release microparticle compositions. The microparticle composition can be formulated to provide extended release over a period of from about 7 days to about 200 days. The microparticles may be formulated with a biodegradable and biocompatible polymer, and an active agent, such as risperidone, 9-hydroxy-risperidone, and pharmaceutically acceptable acidic salts of the foregoing.
U.S. Pat. No. 5,480,656 to Okada provides a microcapsule designed for zero order release of a physiologically active polypeptide over a period of at least two months, which is produced by preparing a water-in-oil emulsion comprising an inner aqueous layer containing about 20 to 70% (w/w) of said polypeptide and an oil layer containing a copolymer or homopolymer having a weight-average molecular weight of 7,000 to 30,000, wherein the composition ratio of lactic acid/glycolic acid in the copolymer or homopolymer is 80/10 to 100/0, and then subjecting said water-in oil emulsion to microencapsulation.
U.S. Pat. No. 5,654,010 to Johnson provides a composition, and methods of forming and using said composition, for the sustained release of biologically active, stabilized human growth hormone (hGH). The sustained release composition of this invention comprises a polymeric matrix of a biocompatible polymer and particles of biologically active, stabilized hGH, wherein said particles are dispersed within the biocompatible polymer. The method of the invention for producing a composition for the sustained release of biologically active hGH, includes dissolving a biocompatible polymer in a polymer solvent to form a polymer solution, dispersing particles of biologically active, stabilized hGH in the polymer solution, and then solidifying the polymer to form a polymeric matrix containing a dispersion of said hGH particles. The method for using a composition of the invention is a method for providing a therapeutically effective blood level of biologically active, non-aggregated hGH in a subject for a sustained period. In this method, a subject is administered an effective dose of the sustained release composition. The method of using the sustained release composition comprises providing a therapeutically effective blood level of biologically active, non-aggregated human growth hormone in a subject for a sustained period by administering to the subject a dose maximum allowed dosage since it may affect the CNS and is contraindicated to be used IV. As Naropin® Injection is often combined with per os taken opiates when administered to treat post-operative pain; it retains some of said sustained release composition.
U.S. Pat. No. 5,538,739 to Bodmer et al discloses microparticles comprising a polypeptide, preferably somatostatin or an analog or derivative thereof, more preferably octreotide, in a polymeric matrix, preferably poly(lactide-co-glycolide) glucose. The invention also discloses sustained release formulations containing said microparticles and the use of said formulations in treating acromegaly and breast cancer.
U.S. Pat. No. 6,132,766 to Sankaram et al. discloses a multivesicular liposome composition containing at least one acid other than a hydrohalic acid and at least one biologically active substance, the vesicles having defined size distribution, adjustable average size, internal chamber size and number, and provides a controlled release rate of the biologically active substance from the composition. The invention also discloses a process for making the composition which features addition of a non-hydrohalic acid effective to sustain and control the rate of release of an encapsulated biologically active substance from the vesicles at therapeutic levels in vivo.
U.S. Pat. No. 5,863,549 to Tarantino is directed to a method for making in vivo a lecithin gel which provides for the sustained release of a biologically active compound contained in the gel. This invention is also directed to a method for the sustained treatment of a human or of other mammals with a therapeutic amount of a biologically active compound using the gel for the sustained release of the biologically active compound. The biologically active compounds disclosed and exemplified are peptides and polypeptides.
US 2005/0287180 to Chen provides compositions that comprise a phospholipid component (that contains one or more phospholipids) and a pharmaceutically acceptable fluid carrier, where the phospholipid component is in the range from about 10% to about 90% of the total weight. The compositions may further comprise non-phospholipid filler materials, where the amount of the non-phospholipid filler materials is in the range from about 5% to about 50% of the total weight. In certain embodiments, the compositions may be injectable, non-liposomal, and/or in form of a gel or a paste. The compositions of the invention may be useful for repairing and augmenting soft and/or hard tissues or for sustained local drug delivery. One drug formulation exemplified is bupivacaine in a phospholipid paste with propylene glycol.
US 2012/0046220 to Chen et al. provides a clear depot comprising at least one hydrophilic water-soluble pharmaceutically active antibacterial agent selected from the group consisting of vancomycin, gentamicin, a pharmaceutically acceptable salt thereof and a mixture thereof, water, a phospholipid, an oil, optionally a pH adjusting agent, and a viscosity modifying agent selected from the group consisting of ethanol, isopropanol, and a mixture thereof, wherein the water present in the final depot formulation is no more than about 4 wt % relative to the total weight of the depot and the depot has a pH of between about 3 and about 6.
US 2012/0316108 to Chen et al. is directed to compositions and methods of preparation of phospholipid depots that are injectable through a fine needle.
Additional references describing phospholipid-based formulations include WO 89/00077, WO 02/32395, EP 0282405 and U.S. Pat. Nos. 4,252,793; 5,660,854; 5,693,337 and Wang et al., Lyophilization Of Water-In-Oil Emulsions To Prepare Phospholipid-based Anhydrous Reverse Micelles For Oral Peptide Delivery, 39 European Journal of Pharmaceutical Sciences, at 373-79 (2010).
The known phospholipid based depot formulations suffer from the drawback of high viscosity making them difficult to administer, and lack of long term stability at ambient temperatures. There is an unmet need for stable depot formulations of hydrophobic active ingredients with improved viscosity and particle size making them amenable to delivery to the required site of action.